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Turning of Retinal Growth Cones in a Netrin-1 Gradient Mediated by the Netrin Receptor DCC

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Turning of Retinal Growth Cones in a Netrin-1 Gradient Mediated by the Netrin Receptor DCC Neuron, Vol. 19, 1211±1224, December, 1997, Copyright 1997 by Cell Press Turning of Retinal Growth Cones in a Netrin-1 Gradient Mediated by the Netrin Receptor DCC Jose R. de la Torre,* Veit H. HoÈ pker,² Guo-li Ming,² project to the midline (Harris et al., 1996; Mitchell et al., Mu-ming Poo,² Marc Tessier-Lavigne,*§ 1996). In addition to their apparent roles in attraction, ³ ² Ali Hemmati-Brivanlou, and Christine E. Holt k the netrins have been implicated as repellents of axons *Howard Hughes Medical Institute that migrate away from the midline in both C. elegans Departments of Anatomy and vertebrates (Colamarino and Tessier-Lavigne, 1995; and of Biochemistry and Biophysics Wadsworth et al., 1996; Varela-Echavarria et al., 1997). University of California Furthermore, genetic and biochemical evidence sug- San Francisco, California 94143-0452 gests that the attractive and repulsive actions of netrin ² Department of Biology proteins might involve different functional domains of University of California the netrin molecules and may be mediated by distinct San Diego, California 92039 receptor mechanisms (Hedgecock et al., 1990; Leung- ³ The Rockefeller University Hagesteijn et al., 1992; Chan et al., 1996; Keino-Masu New York, New York 10021-6399 et al., 1996; Kolodziej et al., 1996; Wadsworth et al., 1996; Ackerman et al., 1997; Leonardo et al., 1997). In addition to this role in midline guidance, studies in a Summary variety of vertebrate species have implicated netrins in guidance in many different regions of the nervous sys- Netrin-1 promotes outgrowth of axons in vitro through tem apart from midline regions (Kennedy et al., 1994; the receptor Deleted in Colorectal Cancer (DCC) and Serafini et al., 1996; Shirasaki et al., 1996; Lauderdale elicits turning of axons within embryonic explants et al., 1997; Livesey and Hunt, 1997; Me tin et al., 1997; when presented as a point source. It is not known Richards et al., 1997; StraÈ hle et al., 1997), including the whether netrin-1 alone can elicit turning nor whether guidance of retinal ganglion cell (RGC) axons into the DCC mediates the turning response. We show that optic nerve head (Deiner et al., 1997). Xenopus retinal ganglion cell growth cones orient Despite the demonstration that netrin proteins are rapidly toward a pipette ejecting netrin-1, an effect required for a number of axon guidance events in vivo, blocked by antibodies to DCC. In vitro, netrin-1 in- the precise role played by netrins in these guidance duces a complex growth cone morphology reminis- events is only partially understood. The cellular aspects cent of that at the optic nerve head, a site of netrin-1 of the apparent attractive function of netrins have been expression in vivo. These results demonstrate that explored in greatest depth in the context of spinal com- netrin-1 can function alone to induce turning, impli- missural axon growth to the ventral midline of the spinal cate DCC in this response, and support the idea that cord. The netrins have two experimentally separable netrin-1 contributes to steering axons out of the retina. activities on spinal commissural axons in vitro. First, these proteins can promote outgrowth of commissural axons from explants of dorsal spinal cord into the Introduction otherwise unfavorable environment of a collagen matrix (Serafini et al., 1994), an apparent ªpermissiveº action Developing axons in the nervous system can be guided (see Discussion). Second, when presented from a point by diffusible factors secreted by target cells, a process source (i.e., transfected cells secreting recombinant known as chemoattraction (reviewed by Tessier-Lavigne netrins), the netrins can cause spinal commissural axons and Goodman, 1996). One family of chemoattractants to reorient growth within the tissue explants over a 40 for developing axons is the netrins, laminin-related hr period (Kennedy et al., 1994), mimicking the chemo- molecules that appear to have a phylogenetically con- tropic or ªturningº activity of floor plate cells (Tessier- served role in guidance of axons in vertebrates, Caeno- Lavigne et al., 1988; Placzek et al., 1990a; Placzek et al., rhabditis elegans, and Drosophila melanogaster. In 1990b). Similar permissive and ªchemotropicº activities rodents, commissural neurons, which are born dorsally have been demonstrated for the effects of netrin-1 on in the spinal cord, extend axons circumferentially toward early cortical efferents (Me tin et al., 1997; Richards et the floor plate at least partly in response to netrin-1 al., 1997), and both may be important for axon guidance secreted by floor plate cells (Tessier-Lavigne et al., in vivo (discussed in Harris et al., 1996; Mitchell et al., 1988; Placzek et al., 1990a, 1990b; Kennedy et al., 1994; 1996; Serafini et al., 1996; Tessier-Lavigne and Good- Serafini et al., 1994, 1996). Similarly, the netrin homolog man, 1996). UNC-6 in C. elegans is required for the proper migration Several aspects of the chemotropic activity of netrins of axons and motile cells toward UNC-6-expressing mid- are poorly understood. First, chemotropic activity has line cells (Hedgecock et al., 1990; McIntire et al., 1992; only been demonstrated on axons growing within ex- Wadsworth et al., 1996), and in Drosophila, loss of func- plants of neural tissue, not in a cell-free environment tion of Netrin-A and Netrin-B, normally expressed at (Kennedy et al., 1994; Me tin et al., 1997), raising the the midline, results in misrouting of axons that normally possibility that the tissue explant provides accessory factors that are necessary for the turning effect. Second, § To whom correspondence should be addressed. the receptor mechanisms that mediate the turning re- sponse have not been defined. Previous studies have k Present address: Department of Anatomy, University of Cam- bridge, Cambridge, United Kingdom CB2 3DY. shown that the netrin receptor Deleted in Colorectal Neuron 1212 Cancer (DCC) expressed by commissural and RGC ax- is most similar to that of netrin-1 proteins in chicken, ons is required for the outgrowth-promoting activity of mouse, and zebrafish (Figure 1; Table 1), suggesting netrin-1 on those axons, since antibodies to DCC mark- that it is the netrin-1 ortholog in Xenopus. Northern blot edly reduce the amount of axon outgrowth from dorsal analysis detected a single transcript of approximately spinal cord or retinal explants that is elicited by netrin-1 2.3 kb from stage 28 mRNA (Figure 2A). Reverse tran- (Keino-Masu et al., 1996; Deiner et al., 1997). It has not, scription PCR (RT-PCR) indicated that netrin-1 is pres- however, been resolved whether DCC also mediates the ent as a maternal transcript (Figure 2B; stage 2, lane 1) turning response of commissural axons toward sources but disappears within the first few cell cycles (data not of netrin-1 in vitro. In a previous study, function-blocking shown) and is largely absent at the midblastula transition antibodies to DCC failed to abolish turning of rat com- (stage 9, lane 2). In contrast to chick embryos (Kennedy missural axons within dorsal spinal cord explants to- et al., 1994), Xenopus netrin-1 transcripts do not appear ward cells secreting netrin-1 (Keino-Masu et al., 1996), to be expressed during gastrulation (stage 10.5, lane suggesting either that DCC is not involved in this turning 3) and only begin to accumulate at stage 11 (lane 4), response or that these antibodies penetrated poorly into increasing in abundance throughout late gastrulation the explant. (stage 12, lane 5), neurulation (stages 13±20; lanes 6±13), To address these issues, we have studied the re- and swimming tadpole stages (stages 33±40; lanes sponses of individual growth cones to netrin-1 protein 16±17). in vitro, focusing on the role of netrin-1 and DCC in the Whole-mount RNA in situ hybridization was used to guidance of retinal axons in Xenopus laevis. Netrin-1 localize netrin-1 transcripts. Netrin-1 transcripts can and DCC are expressed in the developing eye in a variety first be detected by in situ hybridization by stage 12 in of vertebrate species (Kennedy et al., 1994; Pierceall et two stripes on either side of the neural plate midline al., 1994; Keino-Masu et al., 1996; Deiner et al., 1997; (Figure 3A, arrows). Two medio-lateral stripes are also Lauderdale et al., 1997; Livesey and Hunt, 1997; StraÈ hle visible in the anterior neural plate (Figure 3A, arrow- et al., 1997) and have been implicated in retinal axon heads), possibly corresponding to the expansion of guidance into the optic disc in rodents (Deiner et al., netrin-1 expression to the lateral neural plate (Figures 1997). We report here the identification of a Xenopus 3C and 3D, arrowheads) and later to the dorsal midline homolog of netrin-1 and show that, as in rodents, in the caudal diencephalon (Figures 3E, 3F, 3I, and 4I, netrin-1 is expressed in the optic nerve head (disc) and arrowheads). Similar patterns of netrin-1 expression are optic nerve, and DCC is expressed by RGC axons, con- also observed in other vertebrates (Kennedy et al., 1994; sistent with their playing a role in Xenopus RGC axon Serafini et al., 1996; Lauderdale et al., 1997; StraÈ hle et guidance similar to that shown in mouse (Deiner et al., al., 1997). Interestingly, expression in the developing 1997). To examine at a cellular level how growth cones axial mesoderm, particularly in the notochord, appears respond to netrin-1, we have taken advantage of an experimental system in which growth cones of embry- to be absent in Xenopus embryos (Figure 3G), similar onic Xenopus neurites are exposed to stable gradients to zebrafish (StraÈ hle et al., 1997) but contrary to what of soluble chemoattractants established by a calibrated is observed in amniote embryos (Kennedy et al., 1994; pulsatile release mechanism from a small glass capillary Serafini et al., 1996).
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